Disruption of the ciliary GTPase Arl13b suppresses Sonic hedgehog overactivation and inhibits medulloblastoma formation

被引:41
作者
Bay, Sarah N. [1 ,2 ,3 ]
Long, Alyssa B. [1 ]
Caspary, Tamara [1 ]
机构
[1] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA
[2] Emory Univ, Genet & Mol Biol Program, Atlanta, GA 30322 USA
[3] Genet Soc Amer, Bethesda, MD 20814 USA
关键词
Arl13b; cilia; Shh signaling; medulloblastoma; INTRAFLAGELLAR TRANSPORT PROTEINS; BASAL-CELL CARCINOMA; CEREBELLAR DEVELOPMENT; PROGENITOR POOL; NEURAL-TUBE; ARF-FAMILY; MOUSE; DELETION; PATHWAY; ACTIVATION;
D O I
10.1073/pnas.1706977115
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and overactivation of the Sonic Hedgehog (Shh) signaling pathway, which requires the primary cilium, causes 30% of MBs. Current treatments have known negative side effects or resistance mechanisms, so new treatments are necessary. Shh signaling mutations, like those that remove Patched1 (Ptch1) or activate Smoothened (Smo), cause tumors dependent on the presence of cilia. Genetic ablation of cilia prevents these tumors by removing Gli activator, but cilia are a poor therapeutic target since they support many biological processes. A more appropriate strategy would be to identify a protein that functionally disentangles Gli activation and ciliogenesis. Our mechanistic understanding of the ciliary GTPase Arl13b predicts that it could be such a target. Arl13b mutants retain short cilia, and loss of Arl13b results in ligand-independent, constitutive, low-level pathway activation but prevents maximal signaling without disrupting Gli repressor. Here, we show that deletion of Arl13b reduced Shh signaling levels in the presence of oncogenic SmoA1, suggesting Arl13b acts downstream of known tumor resistance mechanisms. Knockdown of ARL13B in human MB cell lines and in primary mouse MB cell culture decreased proliferation. Importantly, loss of Arl13b in a Ptchl-deleted mouse model of MB inhibited tumor formation. Postnatal depletion of Arl13b does not lead to any overt phenotypes in the epidermis, liver, or cerebellum. Thus, our in vivo and in vitro studies demonstrate that disruption of Arl13b inhibits cilia-dependent oncogenic Shh overactivation.
引用
收藏
页码:1570 / 1575
页数:6
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